Viral infections in persons and animals, especially in persons, are widely spread and pose numerous problems for healthcare workers. Pharmaceutical agents capable of effectively and specifically fighting viruses are very limited in number and, moreover, generally cause undesirable secondary effects. Viral infections not only destroy host cells, but also affect the functioning of various proteins and enzymes. Viral invasion favours infection by other pathogenic agents, such as other viruses, bacteria, fungi, etc. Thus, for example, due to the immune loss which it causes, the human immunodeficiency virus (HIV) opens the door to other viruses (herpes simplex, cytomegalovirus, hepatitis B virus) and other pathogenic agents that invade the human body, creating dangerous situations.
Despite intense efforts, thus far it has not been possible to find chemotherapeutic agents which interfere, with an essentially recognisable success, either at the origin or in terms of the symptoms, with the pathogenic episodes caused by viral agents. Therefore, the treatment of viral diseases by chemotherapeutic agents is still incomplete.
Antibody conjugates, formed by a conjugated or hybrid monoclonal antibody and a toxin, have been used to eradicate specific colonies of target cells, directing them against “undesired” target cells that carry surface target antigens and destroying them. The various toxins that have been used by different researchers may be broadly classified into two groups. The first group consists of intact toxins, such as intact ricin. These toxins may not be safely applied in vivo due to their lethal toxicity. The toxins in the second group are called hemitoxins. Hemitoxins are single-strand ribosome-inactivating proteins which act catalytically on eukaryotic ribosomes and inactivate the 60S subunit, leading to a dose-dependent inhibition of the synthesis of cell proteins at the peptide elongation level.
A hemitoxin of interest is the pokeweed antiviral protein (PAP), which is isolated from Phytolacca americana. For many years, it has been recognised that PAP has antiviral activity. It has been demonstrated that PAP blocks the transmission of RNA-containing viruses in plants. It has also been reported that PAP inhibits the replication of two RNA-containing animal viruses: poliovirus and influenza virus, and that PAP inhibits the multiplication of simple herpes viruses type I and type II (U.S. Pat. No. 4,672,053). Although it has been reported that PAP monoclonal antibody conjugates G3.7/CD7, F13/CD14 and B43/CD19 inhibit the replication of HIV-1, these conjugates have turned out to be inconsistent in their capacity to inhibit the replication of the viruses.
In light of the above, the need remains to provide new antiviral compounds or drugs. Advantageously, these new antiviral agents should exhibit an efficacy that is equal to or greater than that of the antiviral agents disclosed in the state of the art and should not cause undesirable secondary effects.
Most prokaryotic and eukaryotic cells encode the uracil DNA glycosylase (UDG) enzyme. The function of this enzyme is to eliminate the uracil residues that appear in DNA due to cytosine deamination or to the incorrect incorporation of dUMP during the replication process. For example, if cytosine deamination occurs and it is not repaired, a C-to-T transition mutation will occur in the DNA strand wherein said deamination has taken place and, consequently, a G-to-A transition mutation will take place in the complementary strand after the next replication round. Once the uracil is eliminated by the UDG enzyme, an apurinic or apyrimidinic site (AP site) is created. The mechanism in charge of repairing these AP sites is the base-splicing repair pathway.
In human cells, up to five different enzymes with UDG activity have been identified. Curiously, one of these enzymes, called UNG2, is present in the particles of the type 1 human immunodeficiency virus (HIV-1). Moreover, some DNA viruses, such as herpesviruses and poxviruses, encode their own UDG activity. As a result of the UDG enzyme's capacity to influence the viral replication of different herpesviruses, said enzyme has been associated with the virus replication mechanism in the host cell. In the above-mentioned viruses, it is known that the UDG enzyme is essential for the infective process. It has been proposed that this enzyme's function in viral replication processes is associated with those viruses' capacity to replicate in non-dividing cells, wherein the levels of cellular UDG enzyme are considered to be low (Priet et al. (2005) Mol. Cell. 17: 479-490) and, consequently, the inhibition thereof is of therapeutic interest. Thus far, some inhibitors of the UDG enzyme encoded by simple herpes virus type 1 (SHV-1) have been designed. These non-protein synthetic compounds have been tested in in vitro systems. On the other hand, it is well-known that the UGI protein encoded by the PBS2 bacteriophage inhibits the UDG enzyme of the SHV-1 virus. However, one disadvantage of this inhibitor is that it also blocks the UDG activity of the human UNG2 enzyme.